Numerous epidemiological and clinical studies have demonstrated a clear relationship between high salt intake and blood pressure. However, the mechanisms of a salt-induced increase in blood pressure--a phenomenon known as salt sensitivity-and the heterogeneity of this effect are far from being completely understood. Recently, evidence accumulated in our laboratory indicates that the anandamide (ANA)- induced activation of vanilloid receptor (VR1) may serve as a novel molecular mechanism mediating sodium and water balance and may play a significant functional role in preventing salt-induced increases in blood pressure. These observations have led to the working hypotheses that increased renal ANA concentration induced by high salt intake activates VR1 receptors and increases CGRP release from sensory nerves innervating the kidney to prevent salt induced increases in blood pressure. Impaired increment of ANA and failure of activation of renal sensory nerves in response to high salt intake occurs in Dahl SS rats, which contributes to increased salt sensitivity of arterial pressure. Four specific aims will be pursued to test the hypotheses that: 1) intra-renal administration of ANA activates VR1 receptors expressed in renal sensory nerves in a dose dependent manner, leading to an increase in renal blood flow and a decrease in blood pressure;2) high salt intake elevates plasma and renal interstitial ANA concentrations and/or increases sensitivity to ANA via increased expression of VR1 or CGRP in renal sensory nerves to enhance natriuretic function;3) ANA activation of renal sensory nerves during high salt intake plays a compensatory role in preventing salt-induced increases in blood pressure;and 4) diminished increment of ANA and/or impaired function of renal sensory nerves in response to high salt intake occurs in Dahl SS rats, which contributes to increased salt sensitivity of arterial pressure. The results of these studies would have far-reaching impacts not only in cardiovascular investigation but also in inflammatory hyperalgesia and pain research given the advancement of our knowledge in this area and the likelihood of new drug discovery.